Abstract Accurate biomarkers for predicting COVID‐19 severity have remained an unmet need due to an incomplete understanding of virus pathogenesis and heterogeneity among patients. Cellular senescence and its pro‐inflammatory phenotype are suggested to be a consequence of SARS‐CoV‐2 infection and potentially drive infection‐dependent pathological sequelae. Senescence‐associated markers in infected individuals have been identified primarily in the lower respiratory tract, while little is known about their presence in more easily accessible bio‐specimens. Here, we measured the abundance of senescence‐associated signatures in whole blood, plasma and peripheral blood mononuclear cells (PBMCs) of COVID‐19 patients and patients without an infection. Bulk transcriptomic and targeted proteomic assays revealed that the level of senescence‐associated markers, including the senescence‐associated secretory phenotype (SASP), is predictive of SARS‐CoV‐2 infection. Single‐cell RNA‐sequencing data demonstrated that a senescence signature is particularly enriched in monocytes of COVID‐19 patients, partially correlating with disease severity. Our findings suggest that monocytes are prematurely induced to senescence by SARS‐CoV‐2 infection, might contribute to exacerbating a SASP‐like inflammatory response and can serve as markers and predictors for COVID‐19 and its sequelae.
Abstract Adipose tissue inflammation and dysfunction are associated with obesity‐related insulin resistance and diabetes, but mechanisms underlying this relationship are unclear. Although senescent cells accumulate in adipose tissue of obese humans and rodents, a direct pathogenic role for these cells in the development of diabetes remains to be demonstrated. Here, we show that reducing senescent cell burden in obese mice, either by activating drug‐inducible “suicide” genes driven by the p16 Ink4a promoter or by treatment with senolytic agents, alleviates metabolic and adipose tissue dysfunction. These senolytic interventions improved glucose tolerance, enhanced insulin sensitivity, lowered circulating inflammatory mediators, and promoted adipogenesis in obese mice. Elimination of senescent cells also prevented the migration of transplanted monocytes into intra‐abdominal adipose tissue and reduced the number of macrophages in this tissue. In addition, microalbuminuria, renal podocyte function, and cardiac diastolic function improved with senolytic therapy. Our results implicate cellular senescence as a causal factor in obesity‐related inflammation and metabolic derangements and show that emerging senolytic agents hold promise for treating obesity‐related metabolic dysfunction and its complications.